1. IFNgamma-Induced IFIT5 Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer via miRNA Processing
- Author
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Lo UG, Pong RC, Yang D, Gandee L, Hernandez E, Dang A, Lin CJ, Santoyo J, Ma S, Sonavane R, Huang J, Tseng SF, Moro L, Arbini AA, Kapur P, Raj GV, He D, Lai CH, Lin H, and Hsieh JT.
- Subjects
IFIT5 ,epithelial-to-mesenchymal transition ,prostate cancer ,miRNA - Abstract
IFNgamma, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFN? can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5'-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFN?-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFN? pathway via a new mechanism of action, which raises concerns about its clinical application.Significance: A unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFN?-induced epithelial-to-mesenchymal transition in prostate cancer.
- Published
- 2019